Process for the preparation of 3-(3-chloro-1h-pyrazol-1-yl)pyridine

ABSTRACT

3-(3-Chloro-1H-pyrazol-1-yl)pyridine is prepared by cyclizing 3-hydrazinopyridine.dihydrochloride with commercially available 3-ethoxyacrylonitrile to provide 3-(3-amino-1H-pyrazol-1-yl)pyridine, and by converting the amino group to a chloro group by a Sandmeyer reaction.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 15/389,531filed on Dec. 23, 2016, which is a divisional of U.S. application Ser.No. 14/988,773 filed on Jan. 6, 2016, which is a continuation of U.S.application Ser. No. 14/666,814 filed on Mar. 24, 2015, which is acontinuation of U.S. application Ser. No. 14/517,349 filed on Oct. 17,2014, which claims the benefit of U.S. Provisional Patent ApplicationSer. No. 62/031,533, filed Jul. 31, 2014, the entire disclosures ofwhich are hereby expressly incorporated by reference in thisApplication.

BACKGROUND

The present invention concerns an improved process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine.

US 20130288893(A1) describes, inter alia, certain(3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amides and carbamates and theiruse as pesticides. The route to prepare such compounds involved thepreparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) by the directcoupling of 3-bromopyridine with 3-chloropyrazole. The 3-chloropyrazolewas prepared by a) treating 1H-pyrazole with 2-dimethylsulfamoylchloride and sodium hydride to provideN,N-dimethyl-1H-pyrazole-1-sulfonamide, b) treating theN,N-dimethyl-1H-pyrazole-1-sulfonamide with perchloroethane and n-butyllithium to provide 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide, andc) removing the N,N-dimethylsulfonamide from3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide with trifluoroaceticacid to give the 3-chloropyrazole.

The disclosed process produces low yields, relies on a starting materialthat is difficult to prepare (3-chloropyrazole) and provides a productthat is difficult to isolate in a pure form. It would be desirable tohave a process for preparing 3-(3-chloro-1H-pyrazol-1-yl)pyridine thatavoids these problems.

SUMMARY

The present invention provides such an alternative by cyclizing3-hydrazinopyridine-dihydrochloride with commercially available3-ethoxyacrylonitrile to provide 3-(3-amino-1H-pyrazol-1-yl)pyridine(8a), and by converting the amino group to a chloro group by a Sandmeyerreaction. Thus, the present invention concerns a process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b),

which comprises

a) treating 3-hydrazinopyridine-dihydrochloride

with 3-ethoxyacrylonitrile

in a (C₁-C₄) aliphatic alcohol at a temperature of about 25° C. to about100° C. in the presence of an alkali metal (C₁-C₄) alkoxide to provide3-(3-amino-1H-pyrazol-1-yl)pyridine (8a)

b) treating the 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) in aqueoushydrochloric acid with sodium nitrite at a temperature of about 0° C. toabout 25° C. to provide the diazonium salt (8b)

and

c) treating the diazonium salt (8b) with copper chloride at atemperature of about 0° C. to about 25° C.

DETAILED DESCRIPTION

The present invention provides an improved process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) by cyclizing3-hydrazinopyridine.dihydrochloride with commercially available3-ethoxyacrylonitrile to provide 3-(3-amino-1H-pyrazol-1-yl)pyridine(8a), and by converting the amino group to a chloro group by a Sandmeyerreaction.

In the first step, 3-hydrazinopyridine.dihydrochloride is treated with3-ethoxyacrylonitrile in a (C₁-C₄) aliphatic alcohol at a temperature ofabout 25° C. to about 100° C. in the presence of an alkali metal (C₁-C₄)alkoxide to provide 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a). Whilestoichiometric amounts of 3-hydrazinopyridine.dihydrochloride and3-ethoxyacrylonitrile are required, it is often convenient to use abouta 1.5 fold to about a 2 fold excess of 3-ethoxy-acrylonitrile. Thecyclization is run in the presence of an alkali metal (C₁-C₄) alkoxidebase. It is often convenient to use about a 2 to about a 5 fold excessof base. The cyclization is performed in a (C₁-C₄) aliphatic alcohol. Itis most convenient that the alkoxide base and the alcohol solvent be thesame, for example, sodium ethoxide in ethanol. It is appreciated thatmethoxyacrylonitrile and propoxyacrylonitrile would be suitable foreffecting this cyclization.

In a typical reaction, 3-hydrazinopyridine.dihydrochloride and ananhydrous alcohol are introduced into a reaction vessel and the alkoxidebase is gradually added. The mixture is stirred and the3-ethoxyacrylonitrile is added. The mixture is stirred at about 80° C.until most of the 3-hydrazinopyridine has reacted. The mixture isallowed to cool and the excess base is neutralized with acid. The crude3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) is conveniently isolated andpurified by standard techniques.

The 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) is then converted to thedesired 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) by treatment inaqueous hydrochloric acid with sodium nitrite at a temperature of about0° C. to about 25° C. to provide a diazonium salt followed by treatmentof the diazonium salt with copper chloride at a temperature of about 0°C. to about 25° C. While stoichiometric amounts of reagents arerequired, it is often convenient to use an excess of reagents withrespect to the 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a). Thus, aqueoushydrochloric acid is used in large excess as the reaction medium. Sodiumnitrite is used in about a 1.3 fold to about a 2 fold excess. Copperchloride is used in about 5 mole percent to about 60 mole percentexcess, preferably from about 15 mole percent to about 30 mole percentexcess. The copper chloride may be either copper(I) chloride orcopper(II) chloride. To suppress foaming during the reaction awater-immiscible organic solvent such as toluene or chloroform can beadded during the treatment of the diazonium salt with copper chloride.

In a typical reaction, a mixture of 3-(3-amino-1H-pyrazol-1-yl)pyridine(8a) and aqueous hydrochloric acid are mixed and cooled to about 0° C.An aqueous solution of sodium nitrite is slowly added maintaining thetemperature below about 5° C. The suspension is stirred at about 0° C.for about 2 hours. In a separate vessel, a mixture of copper(I) chlorideand toluene is cooled to about 0° C. and the chilled suspension ofdiazonium salt is added at a rate maintaining the temperature belowabout 5° C. The mixture is allowed to warm to about ambient temperature.After completion of the reaction, the mixture is treated with aqueoussodium hydroxide to adjust the pH to about 8 to about 10. The resultingsolution is extracted with a water-immiscible organic solvent. Afterremoval of the solvent, the 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)can be used directly in the next step or further purified by standardtechniques such as flash column chromatography or crystallization.

The following examples are presented to illustrate the invention.

Examples 1. Preparation of 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a)

To a three-neck round bottomed flask (50 mL) equipped with a refluxcondenser was introduced 3-hydrazinopyridine.dihydrochloride (1.82 g,10.0 mmol) and anhydrous ethanol (10.0 mL). Sodium ethoxide (21 wt % inEtOH, 11.8 mL, 31.5 mmol) was added over 5 minutes and the internaltemperature increased from 23° C. to 30° C. The resultant light brownslurry turned light pink after stirring for 10 minutes.3-Ethoxyacrylonitrile (2.06 mL, 20.0 mmol) was added over 5 minutes andthe internal temperature remained at 30° C. The yellow mixture wasstirred at 78° C. under nitrogen for 5 hours and was then cooled to 15°C. Hydrochloric acid (4 M in 1,4-dioxane, 2.90 mL) was added slowly toquench any excess base forming a light brown suspension. The mixture wasconcentrated under reduced pressure to afford a brown solid. The solidwas partitioned in water (30 mL) and ethyl acetate (50 mL). Theinsoluble light brown solid was collected by filtration to afford thefirst portion of product (0.340 g, >95% pure by NMR). The aqueous layerwas extracted with ethyl acetate (3×50 mL). The combined organicextracts were concentrated to afford dark brown wet solid. The mixturewas suspended in ethyl acetate (10 mL), filtered, and washed withheptane (20 mL) to afford the second portion of product as a brown solid(1.00 g, >95% pure by ¹H NMR). The title compound was obtained as abrown solid (1.34 g, 84%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (d, J=2.4Hz, 1H), 8.33 (dd, J=4.8, 1.2 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.01(ddd, J=8.4, 2.8, 1.2 Hz, 1H), 7.42 (dd, J=8.4, 4.8 Hz, 1H), 5.80 (d,J=2.4 Hz, 1H), 5.19 (bs, 2H, —NH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.7,144.7, 138.0, 136.2, 128.3, 123.9, 123.2, 97.1; EIMS m/z 160 ([M]⁺);HPLC (Zorbax SB-C8 column, P/N: 863954-306; mobile phase: A=water (0.1%formic acid), B=acetonitrile (0.01% formic acid); Gradient from 5 to100% acetonitrile over 15 minutes; flow: 1.0 mL/minute): t_(R)=1.95minutes.

2. Preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)

To a three-neck round bottomed flask (25 mL) was introduced3-amino-1-(3-pyridyl)-pyrazole (0.480 g, 3.00 mmol) and concentratedhydrochloric acid (4.6 mL). The vigorously stirred mixture was cooled to−5° C. using a sodium chloride ice-bath. Sodium nitrite (0.269 g, 3.90mmol) in water (1.3 mL) was added dropwise over 40 minutes whilemaintaining the temperature at −5° C. The resultant dark orange mixturewas stirred for 1 hour between −5° C. and −0° C. and then added dropwiseinto a suspension of copper(I) chloride (0.475 g, 4.80 mmol) inchloroform (4.8 mL) at 25° C. over 15 minutes. The dark green slurry wasstirred at room temperature for 1 hour. Water (10 mL) and chloroform (10mL) was added to the mixture leading to a dark green solution. Theacidic aqueous solution was neutralized by sodium hydroxide (50% inwater) to pH 8 and extracted with chloroform (2×10 mL) and ethyl acetate(3×20 mL). The combined organic extracts were dried over anhydroussodium sulfate and concentrated under reduced pressure to afford crudeproduct as a yellow solid (0.476 g). LC assay using di-n-propylphthalate as internal standard indicated 73.7% purity (0.351 g, 65%): ¹HNMR (400 MHz, CDCl₃) δ 8.94 (d, J=2.8 Hz, 1H), 8.57 (dd, J=4.8, 1.2 Hz,1H), 8.03 (ddd, J=8.4, 2.8, 1.6 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.41(ddd, J=8.4, 4.8, 0.8 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H); EIMS m/z 179([M]⁺); HPLC (Zorbax SB-C8 column, P/N: 863954-306; mobile phase:A=water (0.1% formic acid), B=acetonitrile (0.01% formic acid); Gradientfrom 5 to 100% acetonitrile over 15 minutes; flow: 1.0 mL/minute):t_(R)=6.28 minutes.

What is claimed is:
 1. A process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b),

comprising treating diazonium salt (8b)

with from about 5 mole percent to about 60 mole percent excess of acopper chloride at a temperature of about 0° C. to about 25° C.
 2. Theprocess of claim 1, wherein the copper chloride is in about 15 molepercent to about 30 mole percent excess.
 3. The process of claim 1,wherein the copper chloride is copper (I) chloride.
 4. The process ofclaim 1, wherein the copper chloride is copper (II) chloride.
 5. Theprocess of claim 1, further comprising adding a water immiscible organicsolvent to suppress foaming.
 6. The process of claim 5, wherein thewater immiscible organic solvent is toluene or chloroform.
 7. Theprocess of claim 5, further comprising adding aqueous sodium hydroxideuntil a pH of about 8 to about 10 is achieved.
 8. The process of claim1, wherein the copper chloride is mixed with toluene prior to the stepof treating.
 9. The process of claim 8, wherein the copper chloride ismixed with toluene and cooled to a temperature of about 0° C. prior tothe step of treating.
 10. The process of claim 1, wherein the diazoniumsalt (8b) is in an aqueous suspension.
 11. The process of claim 10,wherein the aqueous suspension is cooled to about 0° C. prior to thestep of treating.
 12. The process of claim 1, wherein the treatingcomprises contacting a mixture of the copper chloride in toluene with anaqueous suspension of the diazonium salt (8b).
 13. The process of claim12, wherein the mixture of the copper chloride in toluene is cooled to atemperature of about 0° C. prior to the step of treating.
 14. Theprocess of claim 12, wherein the aqueous suspension of the diazoniumsalt (8b) is cooled to about 0° C. prior to the step of treating. 15.The process of claim 13, wherein the aqueous suspension of the diazoniumsalt (8b) is cooled to about 0° C. prior to the step of treating. 16.The process of claim 15, wherein the aqueous suspension of the diazoniumsalt (8b) is added to the mixture of the copper chloride in toluene. 17.The process of claim 16, wherein the aqueous suspension of the diazoniumsalt (8b) is added to the mixture of the copper chloride in toluene at arate maintaining the temperature below about 5° C.